KR100612795B1 - Crystalline Efavirenz - Google Patents

Abstract

Epavirens, a potent reverse transcriptase inhibitor, are prepared in crystalline form. Crystalline efavilens exist in several physical forms, represented by Forms 1, 2, 3, 4 and 5 and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions comprising such compounds and methods for their preparation are useful for the treatment of human immunodeficiency virus (HIV).

Reverse transcriptase, proteolytic enzyme, efavilens, x-ray powder diffraction, differential scanning calorimetry

Description

Crystalline Efavirens {Crystalline Efavirenz}

Epavirens, a potent reverse transcriptase inhibitor, are prepared in crystalline form. Crystalline efavilens exist in several physical forms, represented by Forms 1, 2, 3, 4 and 5 and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions comprising such compounds and methods for their preparation are useful for the treatment of human immunodeficiency virus (HIV).

Reverse transcription is a common feature of retrovirus replication. Viral replication requires a reverse transcriptase encoded by the virus, which produces a DNA copy of the viral sequence by reverse transcription of the viral RNA genome. Thus, reverse transcriptase is a clinically relevant goal for chemotherapy of retroviral infections because inhibiting reverse transcriptase encoded by the virus interferes with viral replication.

Epavirens is effective in the treatment of human immunodeficiency virus (HIV), a retrovirus that results in the progressive destruction of the human immune system and consequently the development of AIDS. Effective treatment through inhibition of HIV reverse transcriptase has been shown when using nucleoside based inhibitors such as azidomidine and non-nucleoside based inhibitors. Benzoxazinones, for example epavirens, have been found to be useful non-nucleotide based inhibitors of HIV reverse transcriptase. The chemical name of efavirenz is (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxe represented by the formula (I). Known as Photo-2-ON.

Epavirens are not only very potent reverse transcriptase inhibitors, but also have effects on the resistance of HIV reverse transcriptase. Because of the importance of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a reverse transcriptase inhibitor, There is a need for crystalline forms that exhibit chemical and physical advantages in preparation, purification and formulation.

Treatment or prevention of the disease is accomplished by administering a therapeutically effective amount of efavilens to a human or animal patient in need of treatment or prevention of the disease. Treatment with epavirens can be achieved by use as a single compound, as a pharmaceutical composition component, or in combination with other antiviral agents, immunomodulators, antibiotics and vaccines. The compounds may be administered enterally or parenterally in solid or liquid dosage forms.

Epavirens are not known to exist in the form of stable crystalline polymorphs conventionally. Thus, there is a need for stable crystalline forms of drugs and reliable and reproducible methods of preparation.

Summary of the Invention

In one aspect, the present invention relates to a crystalline evibilens. A related aspect is in the novel crystalline forms of efavilens represented by crystalline forms 1, 2, 3, 4 and 5. These crystalline forms are characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction analysis (X-ray Powder Differential Analysis) and distinguished from each other.

Another aspect of the invention relates to a pharmaceutical composition comprising crystalline efavirenz and its five crystalline forms. The crystalline product of the present invention may be formulated in a conventional solid pharmaceutical dosage form or may be used to prepare a liquid dosage form by combining a therapeutically effective amount of a crystalline drug with a pharmaceutically acceptable carrier. The crystalline product can be administered in a pharmaceutical composition that can be combined with other antiviral agents, immunomodulators, antibiotics or vaccines.

In another aspect, the present invention relates to a method of inhibiting reverse transcriptase, comprising administering an amount of crystalline efavirens sufficient to cause the reverse transcriptase to contact an effective inhibitory amount of the active drug.

In a particular aspect, the invention provides a method for treating a disease associated with retroviral infections and viral replication, such as human immunodeficiency virus, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a novel crystalline form of an epavirenz of the invention. It is related to the method.

An object of the present invention is to provide a host in need of treatment for HIV infection with at least one compound selected from the group consisting of crystalline forms 1, 2, 3, 4 and 5 epavirens and HIV reverse transcriptase inhibitors and HIV protease inhibitors A novel method of treating HIV infection is provided, comprising administering a therapeutically effective combination of the drugs.

<Brief Description of Drawings>

The present invention has been illustrated with reference to the accompanying drawings as follows.

1 is a powder of Form 1 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one It shows the x-ray diffractogram.

2 is a powder of Form 2 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one It shows the x-ray diffractogram.

FIG. 3 is a powder of Form 3 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one It shows the x-ray diffractogram.

4 is a powder of Form 4 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one It shows the x-ray diffractogram.

FIG. 5 is the parallax of Form 1 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Calorimetry Shows thermal analysis.

FIG. 6 is the parallax of Form 2 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Calorimetry Shows thermal analysis.

FIG. 7 shows Form 3 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. Differential calorimetry shows thermal analysis.

FIG. 8 is the parallax of Form 4 of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Calorimetry Shows thermal analysis.

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In a first embodiment, the present invention provides crystalline Form 1 of the crystalline evivirens.

In a preferred embodiment, Form 1 of Crystalline Epavirens is in substantially pure form.

In another preferred embodiment, Form 1 of the crystalline efavirenz is 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2, 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 X-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of ± 0.2 and 24.8 ± 0.2.

In another preferred embodiment, Form 1 of Crystalline Epavirens is characterized by an x-ray powder diffraction pattern substantially consistent with that shown in FIG. 1.

In another embodiment, Form 1 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram with a peak at about 138 ° C to about 140 ° C.

In another preferred embodiment, Form 1 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 5.

In a more preferred embodiment, the crystalline efambiens of Form 1 are 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2, 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 ± Differential scanning calorimetry thermal analysis characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of 0.2 and 24.8 ± 0.2, with peaks from about 138 ° C. to about 140 ° C. It is characterized by.

In another more preferred embodiment, Form 1 of crystalline efavirens is characterized by an x-ray diffraction pattern substantially consistent with that shown in FIG. 1, and further has a peak at about 138 ° C. to about 140 ° C. Differential scanning calorimetry is characterized by a thermal analysis.

In a second embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 1 of crystalline efavirenz and a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, wherein the therapeutically effective amount is from about 1 mg to about 1000 mg of crystalline form 1 of the crystalline efavirenz.

In a more preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, and the therapeutically effective amount is from about 50 mg to about 200 mg of crystalline form 1 of the crystalline efavirenz.

In another more preferred embodiment, the pharmaceutical composition contained in the capsule or compressed into the tablet dosage form contains more than about 10% disintegrant by weight relative to the total dry weight of the dosage form.

In another preferred embodiment, the pharmaceutical composition is in liquid form.

In a more preferred embodiment, the liquid form comprises a liquid excipient comprising from about 0.1 to about 15 weight percent of crystalline form 1 of the crystalline epavelens, and from about 50 to about 99 weight percent of a polyol ester of a heavy chain fatty acid.

In an even more preferred embodiment, the composition is contained in soft gelatin capsules, wherein the polyol esters of the medium chain fatty acids are based on C ₈ to C ₁₀ fatty acid triglycerides.

In yet another preferred embodiment, a liquid form comprising a liquid excipient comprising from about 0.1 to about 15 weight percent of crystalline form 1 of the crystalline epabilens, and from about 50 to about 99 weight percent of a polyol ester of a heavy chain fatty acid, comprises a sweetener. And from about 0.1 to about 50 weight percent.

In another more preferred embodiment, the liquid pharmaceutical composition comprises a liquid excipient comprising from about 0.1 to about 10 weight percent of crystalline form 1 of the crystalline efavirens, and from about 50 to about 99 weight percent vegetable oil.

In an even more preferred embodiment, the pharmaceutical composition is contained in soft gelatin capsules and the vegetable oil is soybean oil or peanut oil.

In yet another preferred embodiment, a liquid pharmaceutical composition comprising a liquid excipient comprising about 0.1 to about 10 weight percent of crystalline form 1 of the crystalline epabilens, and about 50 to about 99 weight percent of vegetable oil, comprises a sweetener about 1.0 to about 50% by weight.

In a third embodiment, the capsule or compressed tablet pharmaceutical dosage form

(a) Form 1 of a therapeutically effective amount of crystalline efavirenz,

(b) surfactants,

(c) disintegrants,

(d) binders, and

(e) contains a lubricant.

In a preferred embodiment, the therapeutically effective amount is from about 50 mg to about 200 mg of crystalline form of crystalline efavirens, the surfactant is sodium lauryl sulfate, the disintegrant is sodium starch glycolate, the binder is lactose, and the lubricant is Magnesium stearate.

In a fourth embodiment, the present invention comprises providing Form 1 of crystalline efavirens in an amount sufficient to cause an HIV reverse transcriptase to contact an effective inhibitory amount of an active drug. Provided are methods for inhibiting viral replication by enzymes.

In a preferred embodiment, the compound is provided to a human or animal patient to inhibit HIV reverse transcriptase in vivo.

In a fifth embodiment, the present invention describes a method of treating human immunodeficiency virus infection comprising administering to a host in need thereof a therapeutically effective amount of Form 1 of crystalline efavirens. .

In a preferred embodiment, Form 1 of Crystalline Epavirens is administered at a dosage of about 1 to about 1000 mg per dose.

In a more preferred embodiment, Form 1 of Crystalline Epavirens is administered at a dosage of about 50 to about 200 mg per dose.

In a sixth embodiment, Form 1 of Crystalline Epavirens is prepared by recrystallization of Epavirens from a hydrocarbon solvent.

In a seventh embodiment, Form 1 of the crystalline efavirenz is

1) recrystallization of the efavirens from a suitable solvent,

2) isolating the crystal, and

3) drying the crystals at an appropriate temperature to obtain Form 1 of crystalline efavirenz in substantially pure form

It is prepared by a method comprising a.

In a more preferred embodiment, the suitable solvent is heptane or a mixture of tetrahydrofuran and heptane, the crystals are isolated by filtration, the suitable temperature is about 70 ° C to about 95 ° C, and substantially pure is 90% pure. Will be beyond.

In the eighth embodiment, Form 1 of the crystalline evivirens is prepared by heating Form 2, 3, 4 or 5 evivirens or mixtures thereof.

In a ninth embodiment, Form 1 of Crystalline Epavirens is prepared by stirring a slurry of Form 2 Epavirens, Form 3 Epavirens, or a mixture thereof in a hydrocarbon solvent.

In a tenth embodiment, the present invention describes crystalline form 2 of the crystalline evivirens.

In a preferred embodiment, Form 2 of the crystalline evivirens is in substantially pure form.

In another preferred embodiment, Form 2 of the crystalline efavilens consists of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 24.1 ± 0.2, and 28.0 ± 0.2 It is characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from the group.

In another preferred embodiment, Form 2 of the crystalline efavirens is characterized by an x-ray diffraction pattern substantially consistent with that shown in FIG. 2.

In another preferred embodiment, Form 2 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram with a peak at about 116 ° C to about 119 ° C.

In another preferred embodiment, Form 2 of crystalline efavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 6.

In a more preferred embodiment, Form 2 of the crystalline evivirens is a group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2 It is characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from and further characterized by differential scanning calorimetry thermograms with peaks at about 116 ° C. to about 119 ° C.

In yet another preferred embodiment, Form 2 of the crystalline epavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 2, further peaking at about 116 ° C. to about 119 ° C. Differential scanning calorimetry is characterized by a thermal analysis.

In an eleventh embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 2 of the crystalline evivirens and a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form and the therapeutically effective amount is from about 1 mg to about 1000 mg of crystalline form 2 of the crystalline efavirenz.

In another preferred embodiment, the pharmaceutical composition is in liquid form and the therapeutically effective amount is from about 0.1 to about 15% of crystalline form 2 of the crystalline efavirenz.

The transcriptase encoded by a virus according to the twelfth embodiment, comprising providing Form 2 of crystalline efavirens in an amount sufficient to cause the HIV reverse transcriptase to contact an effective inhibitory amount of the active drug. It describes a method for inhibiting viral replication by.

In a thirteenth embodiment, the invention comprises administering to a host in need of treatment or prevention of a disease of a virus, such as a human immunodeficiency virus, and other diseases, Form 2 of crystalline efavirens in a therapeutically effective amount. Describe the method of treatment.

In a preferred embodiment, Form 2 of Crystalline Epavirens is administered at a dosage of about 1 to about 1000 mg per dose.

In a fourteenth embodiment, Form 2 of the crystalline evivirens is prepared by a rapid recrystallization method from a saturated alkane solution of the evivirens.

In a preferred embodiment, the rapid recrystallization is

1) dissolving efavirens in a suitable solvent at a suitable temperature to obtain a saturated solution,

2) filtering the saturated solution, and

3) rapidly cooling the saturated solution to produce crystalline Form 2 of the crystalline efavirenz.

In a more preferred embodiment, the suitable solvent is heptane, the suitable temperature is about 70 ° C. to 80 ° C., and rapidly cooling the saturated solution includes contacting the saturated solution with the cold surface.

In a fifteenth embodiment, the invention describes crystalline form 3 of the crystalline efavirens in substantially pure form.

In another preferred embodiment, crystalline form 3 of the crystalline evivirens consists of 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2, 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2 It is characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from the group.

In another preferred embodiment, Form 3 of the crystalline efavirens is characterized by an x-ray diffraction powder pattern substantially consistent with that shown in FIG. 3.

In another embodiment, Form 3 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram with a peak at about 108 ° C to about 110 ° C.

In another preferred embodiment, Form 3 of the crystalline evivirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 7.

In a more preferred embodiment, Form 3 of the crystalline evivirens is a group consisting of 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2, 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2 And an x-ray powder diffraction pattern comprising at least four 2θ values selected from and further characterized by differential scanning calorimetry thermograms with peaks ranging from about 108 ° C to about 110 ° C.

In another more preferred embodiment, Form 3 of the crystalline efavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 3, further peaking at about 108 ° C. to about 110 ° C. Differential scanning calorimetry is characterized by a thermal analysis.

In a sixteenth embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of crystalline form 3 crystalline evivirens and a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, and the therapeutically effective amount is from about 1 mg to about 1000 mg of crystalline form 3 of the crystalline efavirenz.

In another preferred embodiment, the pharmaceutical composition is in liquid form and the therapeutically effective amount is from about 0.1% to about 15% of crystalline form 3 of the crystalline efavirenz.

In a seventeenth embodiment, the invention provides a transcriptase encoded by a virus comprising providing Form 3 of crystalline efavirens in an amount sufficient to cause the HIV reverse transcriptase to contact an effective inhibitory amount of the active drug. It describes a method for inhibiting viral replication by.

A method of treating human immunodeficiency virus infection according to the eighteenth embodiment, the method comprising administering to the host in need thereof a therapeutically effective amount of Form 3 of crystalline efavirens. List it.

In a preferred embodiment, Form 3 of Crystalline Epavirens is administered at a dosage of about 1 to about 1000 mg per dose.

In a nineteenth embodiment, Form 3 of Crystalline Epavirens is prepared by a method of stirring a slurry of Form 1 Epavirens, Form 2 Epavirens, or a mixture thereof in a hydrocarbon solvent and isolating the crystals.

In a preferred embodiment, the hydrocarbon is heptane and the crystals are isolated by filtration.

In a twentieth embodiment, the present invention describes crystalline form 4 of the crystalline evivirens.

In a preferred embodiment, Form 4 of the crystalline efavirens is in substantially pure form.

In another preferred embodiment, Form 4 of the crystalline evivirens is 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 X-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of ± 0.2, 20.6 ± 0.2, and 24.3 ± 0.2.

In another preferred embodiment, Form 4 of the crystalline efavirens is characterized by an x-ray diffraction powder pattern substantially consistent with that shown in FIG. 4.

In another embodiment, Form 4 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram with a peak at about 95 ° C to about 100 ° C.

In another preferred embodiment, Form 4 of crystalline efavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 8.

In a more preferred embodiment, Form 4 of the crystalline evivirens is 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 ± A differential scanning calorimetry column characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of 0.2, 20.6 ± 0.2 and 24.3 ± 0.2, with peaks at about 95 ° C to about 100 ° C. It is characterized by a degree of analysis.

In another more preferred embodiment, Form 4 of crystalline efavirens is characterized by a differential scanning calorimetry thermogram substantially consistent with that shown in FIG. 4, with peaks at about 95 ° C. to about 100 ° C. Differential scanning calorimetry is characterized by a thermal analysis.

In a twenty-first embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 4 of crystalline efavirenz and a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, and the therapeutically effective amount is from about 1 mg to about 1000 mg of crystalline form 4 of the crystalline efavirenz.

In another preferred embodiment, the pharmaceutical composition is in liquid form and the therapeutically effective amount is from about 0.1% to about 15% of crystalline form 4 of the crystalline efavirenz.

The reverse transcriptase encoded by the virus of claim 22, wherein the present invention comprises providing Form 4 of crystalline efavirens in an amount sufficient to cause the HIV reverse transcriptase to contact an effective inhibitory amount of the active drug. It describes a method for inhibiting viral replication by.

The method of embodiment 23, wherein the invention comprises administering to a host in need thereof a therapeutically effective amount of Form 4 of crystalline efavilens in a host in need of treatment or prevention of a human immunodeficiency virus infection. List it.

In a preferred embodiment, Form 4 of Crystalline Epavirens is administered at a dosage of about 1 to about 1000 mg per dose.

In a twenty-fourth embodiment, Form 4 of crystalline efavirenz is prepared by recrystallization from a mixed solvent system.

In embodiment 25, Form 4 of the crystalline efavirenz is

1) adding a suitable solvent to the solution of efavilens to produce the final solution,

2) distilling the final solution into a solvent composition to crystallize the efavirens into crystalline form 4, and

3) isolating the decision

It is prepared by a method comprising a.

In a preferred embodiment, a suitable solvent is heptane, the solution comprises tetrahydrofuran and efavirens, the solvent composition is about 1 to about 10% tetrahydrofuran in heptane and the isolation comprises filtration.

In a twenty-sixth embodiment, the present invention describes crystalline form 5 of the crystalline evivirens.

In another preferred embodiment, Form 5 of the crystalline evivirens is 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2, 20.6 ± 0.2, 21.3 ± 0.2, 22.8 ± 0.2, 24.8 X-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of ± 0.2, 27.4 ± 0.2, 28.2 ± 0.2, and 31.6 ± 0.2.

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In another embodiment, Form 5 of Crystalline Epavirens is characterized by a differential scanning calorimetry thermogram with a peak at about 108 ° C to about 110 ° C.

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In a more preferred embodiment, Form 5 of the crystalline evivirens is 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2, 20.6 ± 0.2, 21.3 ± 0.2, 22.8 ± 0.2, 24.8 ± Characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from the group consisting of 0.2, 27.4 ± 0.2, 28.2 ± 0.2, and 31.6 ± 0.2, with a parallax with peaks at about 108 ° C to about 110 ° C Scanning calorimetry is characterized by thermal analysis.

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In a twenty-seventh embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of Form 5 of crystalline efavirenz and a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, and the therapeutically effective amount is from about 1 mg to about 1000 mg of crystalline form 5 of the crystalline efavirens.

In another preferred embodiment, the pharmaceutical composition is in liquid form and the therapeutically effective amount is from about 0.1% to about 15% of crystalline form 5 of the crystalline epavirens.

The method of claim 28, wherein the present invention comprises providing Form 5 of crystalline efavirens in an amount sufficient to cause the HIV reverse transcriptase to contact an effective inhibitory amount of the active drug. It describes a method for inhibiting viral replication by.

The method of claim 29, wherein the invention comprises administering to a host in need thereof a therapeutically effective amount of Form 5 of crystalline efavirens in a host in need of treatment or prevention of a human immunodeficiency virus infection. List it.

In a preferred embodiment, Form 5 of Crystalline Epavirens is administered at a dosage of about 1 to about 1000 mg per dose.

In the thirtieth embodiment, crystalline Form 5 of the crystalline efavirenz is prepared by recrystallization from a mixed solvent system.

In a thirty-first embodiment, the invention provides a therapeutically effective amount of (a) Form 1, 2, 3, 4 or 5 of crystalline epavirens, and (b) an HIV reverse transcriptase inhibitor to a host in need thereof. A method of treating HIV infection comprising combining and administering one or more compounds selected from the group consisting of HIV protease inhibitors is described.

In a thirty-second embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 1, 2, 3, 4, 5 or a mixture thereof and a pharmaceutically acceptable carrier.

Epavirens is a common name represented by the following general formula (I) (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzox Known as Photo-2-ON.

<Formula I>

Synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one is commercially available It can be achieved using 4-chloroaniline. Reaction with pivaloyl chloride in the presence of hydroxide yields the corresponding amide, which is then treated with alkyl lithium and ethyl trifluoroacetate and acidified with mineral acid to give the salt of trifluoroketone (Scheme 1).

The organic base is then reacted with benzyl alcohol in the presence of an acid to obtain benzylamine and alkylated with cyclopropylethynyl lithium in the presence of a chiral derivative to obtain chiral alcohol (Scheme 2).

Carbinol is oxidized to benzyl imine to promote intramolecular cyclization. The benzyl group is removed and the free amine is cyclized to give the active drug represented by formula (I) (Scheme 3).

A method for synthesizing efavirens is further disclosed in commonly assigned US patent application Ser. No. 60 / 032,980.

Five crystalline forms, identified as crystalline forms 1, 2, 3, 4 and 5, were identified. Each crystalline form can be distinguished from each other by x-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). Each crystalline form can be isolated in substantially pure form under the following conditions. In addition, the crystalline forms may be interconverted by the methods taught herein.

Form 1 is the most thermodynamically stable form. The melting point is about 138 ° C. to about 140 ° C., which is the highest of the four crystalline forms. Because of the increased stability, they are commonly used in drug formulations. All other crystalline forms can be converted to Form 1 during drying at about 60 ° C to about 110 ° C. Conversion and drying are preferably carried out in a dryer oven at about 70 ° C to about 110 ° C under reduced pressure. More preferred temperatures are about 75 ° C to about 85 ° C. Form 5 is converted to Form 1 by heating to 95 ° C. under reduced pressure. Forms 2 and 3 may also be converted to Form 1 using a hydrocarbon slurry at about 65 ° C. to about 75 ° C. Heptane is the most preferred hydrocarbon for this conversion. However, Form 4 cannot convert to Form 1 under these conditions because it is solubilized at about 70 ° C. Form 1 may crystallize directly from heptane when the saturated solution is seeded at about 60 ° C. to about 75 and maintained at this temperature until Form 1 crystallizes.

Form 2 can be obtained by rapid crystallization. Rapid crystallization can be achieved by filtering the saturated heptane solution of efavirens at about 70 ° C. to about 80 ° C., and crystallization preferably occurs when the solution comes in contact with the cooler surface. Melting point of Form 2 is about 116 ° C. to about 119 ° C., as observed by differential scanning calorimetry, which is therefore quite stable. The bed is generally larger than the other crystalline forms. Form 2 is free of many impurities commonly found in the process of forming an efavilens. Thus, Form 2 is an important instrument for the commercial preparation of efavilens associated with the purification of secondary harvests and the recovery of batches in which the drug is not processed. In addition, larger crystals confer a number of process advantages, such as shorter filtration and drying times and improved flowability of the slurry solution. Form 2 can be converted to Form 1 by heating from about 95 ° C. to about 100 ° C. for about 15 hours in a drier. In contrast, Form 1 can be prepared from Form 2 by slurrying Form 2 in heptane heated to about 70 ° C. and holding at this temperature for about 2 hours. The preferred concentration of this slurry is about 12 mL of solvent per gram of Form 2 Epavirens. Form 2 can also be converted to Form 3 by slurrying in heptane at room temperature for about 8 hours to about 24 hours. Form 2 was slurried Form 2 in heptane such that a concentration of about 10 mL of solvent per gram of epavirens was obtained, and THF was added to reach a concentration of about 4 to 6 mL of THF in about 100 mL of heptane / THF solution. Can be converted to

Form 3 can be obtained by stirring the hydrocarbon slurry of Form 1 or Form 2 at about 25 ° C. Heptane is the most preferred hydrocarbon. In general, Form 2 converts to Form 3 faster than Form 1. This conversion takes about 8 hours to about 24 hours. The transition from Form 1 to Form 3 takes at least about 48 hours. Melting point of Form 3 is about 108 ° C. to about 110 ° C., as observed by differential scanning calorimetry, and is the most stable form in the slurry solution of efavirens at room temperature. Form 3 may be converted to Form 1 by drying at about 85 ° C. to about 90 ° C. for about 12 hours to about 24 hours. Conversion from Form 3 to Form 1 can also be accomplished by heating a heptane slurry at a concentration of about 10 mL to about 14 mL of solvent per gram of Form 3 Efavirens and maintaining the slurry at this temperature for about 2 hours.

Melting point of Form 4 is about 95 ° C. to about 100 ° C. when observed by differential scanning calorimetry. Form 4 is the most suitable form and drying leads to process advantages associated with the handling of crystalline materials. In addition, Form 4 forms the preferred crystalline phase and is therefore particularly suitable for formulation. Crystals can be obtained from a hydrocarbon slurry of Form 1 or Form 2 when cyclic ethers such as tetrahydrofuran (THF) are added to give about 4 to about 6% THF relative to the hydrocarbon (v / v) solvent composition. Heptane is the most preferred hydrocarbon. Crystallized directly from about 5% THF in heptane solution. Since the solubility of efavirens in the THF / heptane mixture is generally high, it is desirable to carry out specific process protocols to maximize yield. Once Form 4 crystallizes, it is desirable to lower the THF concentration to less than about 1%, which is accomplished by replacing the solvent with heptane. Form 4 is also obtained by crystallization from a saturated solution in methylcyclohexane. Recrystallization from straight chain heptane generally forms Form 4, 1, 2 or mixtures thereof. Form 4 is the form that is isolated as a wet cake in the manufacture of commercial drugs, as efavirins are the most commonly produced form when crystallized from a hydrocarbon / THF mixture. Form 4 may be converted to Form 1 by drying the crystals at about 80 ° C. to about 100 ° C. for about 12 hours to about 24 hours, preferably in a vacuum dryer. In order to produce on a large scale from Form 1 to Form 4, it is desirable to treat the wet cake of Form 4 by heating to release most of the solvent, and then to bring the temperature to about 80 ° C. to about 100 ° C. to complete the conversion. Can be raised.

The melting point of Form 5 is about 108 ° C. to about 110 ° C. when observed by differential scanning calorimetry. Form 5 was found to be the thermodynamic most stable crystalline form below 40 ° C. Form 5 has high crystallinity and has desirable additional properties that remove impurities to yield the benefits of processed sand. Crystals can be obtained by recrystallization from a dilute solution of THF / heptane. Crystals can be obtained from solutions in which Form 1 or Form 4 is pre-isolated.

Possible interconversions of the crystalline forms of the invention can be further understood by reference to Scheme 4.

Justice

The following abbreviations are used herein: "THF" is intended to mean tetrahydrofuran, "GC" is used to mean gas chromatography, and "DMSO" means dimethylsulfoxide. "TMEDA" is intended to mean N, N, N ', N'-tetramethylethylenediamine.

The term "hydrocarbon" as used herein refers to an alkane solvent. Such examples include, but are not limited to, solvents such as pentane, hexane, heptane, octane, nonane, decane and the like. Preferred mixed solvent systems in the present invention are mixed solvent systems containing tetrahydrofuran and hydrocarbons.

As used herein, the term “slurry” is intended to mean a saturated solution of efavilens and an additional amount of efavilens that provides a heterogeneous solution of Efavirenz and solvent.

The present invention describes substantially pure forms of crystalline form 1, crystalline form 2, crystalline form 2, crystalline form 3, crystalline form 4, crystalline form 5 and crystalline form 5. As used herein, the term “substantially pure” refers to compounds having a purity greater than 90%, including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100%.

When the efavilens dissolve, it loses the crystalline structure and is therefore referred to as the efavilens solution. However, all forms of the present invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, crystalline evivirens may be incorporated into the solid formulation.

A therapeutically effective amount of crystalline efavilens is combined with a pharmaceutically acceptable carrier to produce a pharmaceutical composition of the present invention. A "therapeutically effective amount", when administered alone or in combination with additional therapeutic agents, means an amount effective to prevent, inhibit or ameliorate the disease or condition, or the progression of the disease or condition. The combination of the compounds used herein is preferably a synergistic combination. For example, the synergistic effect as described in Chou and Talalay, Adv. Enzyme Regul. 22: 27-55 (1984), is the effect of the compound when administered in combination (in this case, inhibition of HIV replication). Occurs when the is greater than the sum of the compound effects when administered alone as a single substance. In general, synergy is most clearly demonstrated at sub-optimal concentrations of the compound. Synergistic effects can be seen in terms of low cytotoxicity, increased antiviral effect or some other beneficial effect of the formulation compared to the individual components.

The compounds of the present invention are useful for the inhibition of HIV reverse transcriptase, for the treatment of infection by human immunodeficiency virus (HIV), and for the treatment of subsequent pathological conditions such as acquired immunodeficiency syndrome (AIDS). Treatment of AIDS or infection by HIV can be attributed to a wide range of symptoms of asymptomatic HIV infection, asymptomatic and asymptomatic AIDS, ARC (AIDS-related syndrome), and blood transfusions, fluid exchange, bite wounds, needle-stick accidents, or intraoperative blood exposure. It is defined as including but not limited to treating and preventing actual or potential exposure to HIV.

For this purpose, the compounds of the present invention are administered orally, parenterally (subcutaneously, intravenously) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable auxiliaries and excipients, all of which are known to those skilled in the pharmaceutical arts. Or intramuscular, intrasternal injection or infusion techniques), by inhalation spray or rectally.

The crystalline forms of epavirens described herein can be formulated into pharmaceutical compositions and used in methods of treatment and prevention as described in US Pat. No. 5,519,021, which is incorporated herein by reference. Such methods include the use of the forms of the invention in combination with one or more substances useful for treating AID, such as other HIV reverse transcriptase inhibitors, HIV protease inhibitors, antiviral agents, immunomodulators, anti-infective antibiotics or vaccines. do.

As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T and 3TC. Examples of non-nucleoside RT inhibitors include delaciadin (Pharmacia and Upjohn U90152S), nevirapine (manufactured by Boehringer Ingelheim), Ro 18,893 (manufactured by Roche), trovirdin (manufactured by Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co., Ltd.) and MEN 10979 (Menarini Farmaceutici) It is not limited to this.

As used herein, "HIV protease inhibitor" is intended to refer to a compound that inhibits HIV protease. Examples include Saquinavir (Roche, Ro31-8959), Litonavir (Abbott, ABT-538), Indinavir (Merck, MK-639), Amprenavir (Vertex / Glaxo Wellcome), and Nelfinavir ( Agouron, AG-1343), Palinavir (manufactured by Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG- 71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn) ) And ABT-378. Further examples include cyclic protease inhibitors disclosed in WO93 / 07128, WO94 / 19329, WO94 / 22840 and PCT Application No. US96 / 03426.

The crystalline forms of the efavirens of the present invention may be in oral dosage forms such as tablets, capsules (each containing sustained or active agents), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. May be administered.

Solid dosage forms suitable for administration (pharmaceutical compositions) may generally contain from about 1 to about 1000 mg of crystalline efavilens per dosage unit.

For oral administration in solid form, such as tablets or capsules, crystalline efavirens are nontoxic such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. It may be combined with a pharmaceutically acceptable inert carrier.

Preferably, in addition to the active ingredient, solid dosage forms contain many additional ingredients referred to herein as "excipients". Such excipients include in particular diluents, binders, lubricants, lubricants and disintegrants. Colorants may also be incorporated. As used herein, "diluent" is a substance that imparts bulk to the formulation to have a practical size for compacting tablets. Examples of diluents are lactose and cellulose. As used herein, a "binder" is a material used to impart cohesiveness to a material in powder form so that the tablets remain in close contact after compression and improve the free flow of the powder. Examples of conventional binders are lactose, starch and various sugars. As used herein, "lubricant" has several functions, including preventing tablets from adhering to the compression device and improving the flow of granules prior to compression or encapsulation.Lubricants are in most cases hydrophobic materials. Silver can result in agents that reduce disintegration of the drug and / or delay dissolution A " lubricant " as used herein is a substance that improves the flow properties of the granular material Examples of glidants are talc and colloidal “Disintegrants” as used herein are substances or mixtures thereof added to the formulation to facilitate destruction or disintegration of the solid dosage form after administration. Clays, cellulose, algins, gums and crosslinked polymers One type of disintegrant, referred to as a "super-disintegrant", is generally solid It is usually used at a low level of 1 to 10% by weight relative to the total weight of the dosage unit in the form.Croscarmellose, crospovidone and sodium starch glycolate represent examples of crosslinked cellulose, crosslinked polymer and crosslinked starch, respectively. Sodium starch glycolate swells 7-12 times in less than 30 seconds while effectively disintegrating the granules containing it.

Disintegrants preferably used in the present invention are selected from the group comprising modified starch, croscarmellose sodium, carboxymethylcellulose calcium and crospovidone. More preferred disintegrants in the present invention are modified starches such as sodium starch glycolate.

Preferred carriers include capsules or compressed tablets having a solid pharmaceutical dosage form as used herein. Preferred capsule or compressed tablet forms generally comprise a therapeutically effective amount of efavilens and one or more disintegrants greater than about 10% by weight, based on the total weight of the capsule content or the total weight of the tablet.

Preferred capsule formulations may contain about 5 to about 1000 mg of efavilens per capsule. Preferred compressed tablet formulations contain about 5 to about 800 mg of efavilens per tablet. More preferred formulations contain about 50 to about 200 mg of efavilens per capsule or compressed tablet. Preferably, the capsule or compressed tablet pharmaceutical dosage form comprises a therapeutically effective amount of Epavirens of Form 1, 2, 3 or 4; Surfactants; Disintegrants; Binders; Lubricants and optionally additional pharmaceutically acceptable excipients such as diluents, lubricants and the like, and the disintegrants are selected from modified starch, croscarmellose sodium, carboxymethylcellulose calcium and crospovidone.

Generally, liquid pharmaceutical compositions for oral administration have from about 0.1 to about 15 weight percent HIV reverse transcriptase inhibitor. More preferably, the drug component may be present in the composition in about 1 to about 10 weight percent.

When administered orally in liquid form, the crystalline efavirens may be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In a preferred liquid composition, the liquid excipient consists essentially of polyol esters of medium chain fatty acids. The term "polyol esters of medium chain fatty acids" is intended to include esters or mixed esters of other open chain polyols, such as glycerol, propylene glycol, or polyethylene glycols reacted with medium chain fatty acids having a chain length of 6 to 12 carbon atoms. Especially preferred for the composition are triglycerides or diglycerides of C ₈ -C ₁₀ fatty acids commercially available from fractionation of coconut oil. Such commercially available products are conventional in the formulation of about 68% C ₈ fatty acid (caprylic acid) triglycerides and about 28% C ₁₀ fatty acid (capric acid) triglycerides and trace amounts of C ₆ and C ₁₄ fatty acid triglycerides. Commercially available under the trade names "Miglyol" and "Captex 300" having the composition.

When present, the heavy chain fatty acid ester component acts as a solvent excipient for the active agent in preparing the compositions of the present invention and is present in the composition at about 50 to about 99 weight percent, preferably 70 to 99 weight percent.

Preferably, liquid compositions containing polyol esters may contain sweetening agents useful for reducing the oil taste of the medium chain fatty acid esters, which contributes significantly to making the compositions more delicious.

Sweeteners may be selected from sugars such as sucrose, mannitol, sorbitol, xylitol, lactose and the like, sugar substitutes such as cyclamate, saccharin, aspartame and the like. When sugar substituents are selected as sweeteners, the amount used in the compositions of the present invention may be substantially less than when sugars are used. In consideration of this, the sweetening agent may be used in the composition 0.1 to 50% by weight, preferably 0.5 to 30% by weight.

More preferred sweeteners are sugars, in particular sucrose. The particle size of sucrose in powder form used has been found to have a significant effect on the material appearance and final taste judgment of the final composition. The preferred particle size of the sucrose component used is a mesh US standard screen of 200 to less than 325.

In another preferred liquid pharmaceutical composition, efavirens is combined with a liquid excipient which is a vegetable oil selected from the group consisting of olive oil, peanut oil, soybean oil, corn oil, safflower oil, sunflower oil, canola oil or walnut oil. Such vegetable oils are commercially available from many sources known to those skilled in the art.

The vegetable oil component acts as a solvent excipient for the active agent in preparing the composition of the present invention and is present in the composition at 50 to 99% by weight, preferably 70 to 99% by weight.

Preferably, pharmaceutical compositions containing vegetable oils also contribute significantly to making the compositions more delicious by containing sweetening agents useful for reducing the oil taste of vegetable oils.

The liquid composition may also contain other ingredients commonly used to prepare pharmaceutical compositions. One example of such an ingredient is lecithin. The use of an emulsifier in the composition of the present invention at 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight, may possibly improve the absorption of the active drug. Other examples of ingredients that can be used include antimicrobial preservatives such as benzoic acid or parabens; Suspending agents such as colloidal silicon dioxide; Antioxidants; Local oral anesthetics; Flavoring agents; And colorants.

The selection of such optional components and the level of use in the compositions of the present invention are within the ability of those skilled in the art and can be further considered from the examples set forth below.

Crystalline efavirens can also be combined with soluble polymers as target drug carriers. Such polymers may include polyvinylpyrrolidin pyran copolymers, polyhydroxypropylmethacrylamide-phenols, polyhydroxyethyl-aspartamidephenols or polyethylene oxide-polylysine substituted with palmitolyl residues. In addition, crystalline epavirens are a type of biodegradable polymer useful for controlling the release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid , Polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels can be combined with crosslinked or amphiphilic block copolymers.

Gelatin capsules of crystalline efavirens may contain efavirins and the liquid or solid compositions described herein. Gelatin capsules may also contain carriers in powder form, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Tablets and capsules can be prepared as sustained release products to release the drug continuously for a period of time. Tablets may be coated with sugar or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere or may be enteric coated for selective disintegration in the gastrointestinal tract.

Generally, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Parenteral solutions are prepared by dissolving the crystalline evivirens in a carrier and, if necessary, adding a buffer material. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl- or propyl-parabens and chlorobutanol.

Suitable pharmaceutical carriers are described in the standard literature in this field (Remington's Pharmaceutical Sciences, Mack Publishing Co.). Useful dosage forms for administering the compounds of the present invention can be described as follows:

capsule

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules with 100 mg of the active ingredient in powder form, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

Mixtures of the active ingredients in digestible oils such as soybean oil, cottonseed oil or olive oil can be prepared and injected into the gelatin by a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. After that, the capsules are washed and dried.

refine

A large number of tablets are administered so that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Could be prepared as. Appropriate coatings may be applied to increase taste or delay absorption.

Suspension

Each 5 mL of an aqueous suspension for oral administration contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P. And 0.025 mg of vanillin.

Injection

Parenteral compositions suitable for injection administration can be prepared by stirring 10% by volume of propylene glycol and 1.5% by weight of active ingredient in water. The solution is sterilized by conventional techniques.

Nasal spray

Aqueous solutions are prepared such that each 1 mL contains 10 mg of active ingredient, 1.8 mg of methylparaben, 0.2 mg of propylparaben and 10 mg of methylcellulose. Dispense the solution into 1 mL bottles.

Lung inhaler

A uniform mixture of active ingredients in polysorbate 80 is prepared such that the final concentration of active ingredient is 10 mg per container and the final concentration of polysorbate 80 in the container is 1% by weight. The mixture is dispensed into each can, the valve is crimped onto the can and the required amount of dichlorotetrafluoroethane is added under pressure.

Combination of Components a) and b)

The therapeutic component a) of crystalline forms 1, 2, 3, 4, 5 of the present invention may be any dosage form independently as disclosed above, and may also be administered in various combinations as described above. In the following description, component b) is understood to represent one or more substances as described above. Thus, when the components a) and b) are treated together or independently, the respective substances of the component b) can also be treated together or independently.

Components a) and b) of the invention can be prepared together in a single dosage unit as a combination product (ie can be combined together in one capsule, tablet, powder or liquid, etc.). If components a) and b) are not prepared together in a single dosage unit, component a) is administered simultaneously with component b) or in any order, for example, component a) of the present invention first, followed by component b). ) Or in reverse order. If component b) contains at least one substance, for example one RT inhibitor and one protease inhibitor, these substances may be administered together or in any order. If not administered simultaneously, administration of components a) and b) is preferably carried out at intervals of less than about 1 hour. Preferably, the route of administration of components a) and b) is oral. As used herein, the term oral agent, oral inhibitor, oral compound and the like refer to compounds that can be administered orally. It is preferred to administer component a) and component b) by the same route (eg both orally) or dosage forms, but if necessary different routes (eg, one component of the combination may be administered orally, and the other The components may be administered intravenously) or in dosage forms, respectively.

As will be understood by the pharmaceutical manufacturers in the art, the dosage of the formulations of the present invention may vary depending on the pharmacodynamic properties and the mode and route of administration, the age, health and weight of the patient, and the nature of the symptoms as described above. And degree, the type of concurrent treatment, the number of treatments and the desired effect.

Suitable dosages of components a) and b) of the present invention can be readily determined by one skilled in the art based on the description of the present invention. As a general guideline, typically the daily dosage may be from about 100 mg to about 1.5 g of each component. If component b) represents one or more compounds, typically the daily dose may be from about 100 mg to about 1.5 g of each substance of component b). As a general guideline, when a compound of component a) and component b) is administered in combination, the dosage of each component is conventional for the component when administered alone as a single substance for the treatment of HIV infection in view of the synergistic effect of the formulation. It can be reduced by about 70-80% compared to the phosphorus dose.

Combination products of the present invention can be prepared so that the active ingredient is formulated in a single dosage unit but physical contact between the active ingredients is minimized. For example, when oral administration of a product, one active ingredient may be enteric coated to minimize contact. Enteric coating of one of the active ingredients not only minimizes contact between the blended active ingredients, but also releases one of these ingredients from the gastrointestinal tract so that one of these ingredients is not released in the stomach, but rather in the intestine. It is possible to adjust. Another embodiment of the present invention in which oral administration is preferred provides a formulation product in which one of the active ingredients is coated with a sustained release material throughout the gastrointestinal tract and acts to minimize physical contact between the blended active ingredients. In addition, the sustained release component may be further enterically coated such that release of such component occurs only in the intestine. Another approach is to coat one component with a sustained release and / or enteric release polymer to further separate the active ingredients, and the other component also has a low viscosity grade of hydroxypropyl methylcellulose or other suitable material known in the art. Coating with a polymer such as The polymer coating acts to form additional barriers to interaction with other components. In the case of preparations in which contact between components a) and b) is prevented through a coating or some other material, contact between each of the components of component b) can be prevented.

Dosage forms of the inventive combination product in which one active ingredient is enteric coated may be compressed after the enteric coated component and other active ingredients are mixed together, or the other active ingredient may be added after the enteric coated component is compressed into a tablet layer. It may be in the form of a compressed tablet. Optionally, one or more placebo layers may be present between the active ingredient layers to further separate the two layers. In addition, the dosage form of the present invention may be in the form of a capsule in which one active ingredient is compressed into tablets or in the form of a plurality of fine tablets, particles, granules or non-perils which are subsequently enteric coated. . The enteric coated fine tablets, particles, granules or non-peryl agents are then encapsulated or compressed into capsules with granules of other active ingredients.

Whether administered in a single dosage form or administered simultaneously in separate forms, these and other methods of minimizing contact between the formulation components of the present invention are readily apparent to those skilled in the art based on the present disclosure. Will be.

Also included within the scope of the present invention are pharmaceutical kits useful for the treatment of HIV infection comprising a therapeutically effective amount of a pharmaceutical composition containing a compound of component (a) and at least one component (b) compound in at least one sterile container. Sterilization of the vessel can be carried out using conventional sterilization methods well known to those skilled in the art. Component (a) and component (b) may be present in the same sterile container or in separate sterile containers. The sterile container of material may comprise a separate container or, if desired, one or more multi-part containers. Component (a) and component (b) may be separated or physically mixed in a single dosage form or unit as described above. Such kits may further comprise one or more of various conventional pharmaceutical kit components (eg, one or more pharmaceutically acceptable carriers, additional vials for mixing ingredients, etc.), as required, which will be appreciated by those skilled in the art. Will be easily apparent to Instructions describing the amount of ingredient administered and guiding administration and / or mixing of the ingredients may also be included in the kit as an insert or label.

Obviously, various changes and modifications of the present invention are possible within the scope of the above teachings. Accordingly, it is to be understood that the invention is to be practiced within the scope of the appended claims rather than specifically described herein.

Analytical Method

X-ray powder diffraction

X-ray powder diffraction data of Epavirens was obtained using a Philips Model 3720 automated powder diffractometer. Samples were run in batch mode on a Model PW 1775 multi-position sample changer. The diffractometer was equipped with a variable slit (θ-compensation slit), a scintillation counter and a graphite monochromator. Radiation used CuK α (40 kV, 30 mA). At room temperature, data were collected with 2θ of 2 to 60 degrees, step size of 0.02 degrees, and stepwise counting time of 0.5 seconds. Samples were prepared as thin layers of solvent-free powder material on a glass sample vessel.

Differential scanning calorimetry

The thermal properties of efavirens were characterized by differential scanning calorimetry using a TA Instruments DSC 910, and the data analyzed using a TA Instruments Thermal Analyzer 2100. . Using an empty aluminum dish as a control, the sample was placed on a sealed aluminum dish and analyzed. Heated at a heating rate of 5 ° C. to 10 ° C. per minute at a temperature ranging from 25 ° C. to 200 ° C. The device was calibrated to indium standards.

The following examples are for the preparation of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. It is about.

Example 1 Preparation of N- (4-Chlorophenyl) -2,2-dimethyl Propanamide

Dissolve 4-chloroaniline (52.7 kg, 413 mol) in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg) and cool to 15 ° C. It was. While maintaining the temperature below 40 ° C., the resulting slurry was charged with trimethylacetyl chloride (52.2 kg, 448 mol) over 1 hour. After stirring at 30 ° C. for 30 minutes, the slurry was cooled to −10 ° C. and maintained for 2 hours. The product was collected by filtration and washed with a mixture of water / methanol (90/10) (175 kg) and then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid.

Example 2 Preparation of Hydrochloride Hydrate of 4-Chloro-2-trifluoroacetylaniline

To a solution of TMEDA (20.2 kg, 174 mol) in anhydrous t-butyl methyl ether (271.5 kg) was charged N- (4-chlorophenyl) -2,2-dimethyl propanamide (36.7 kg, 173 mol) and -20 ° C Cooled to. To the cold slurry was added 2.7 N n -butyllithium (101.9 kg, 393 mol) in hexanes while maintaining the temperature below 5 ° C. After aging at 0-5 ° C. for 2 hours, the solution was cooled to below −15 ° C. and rapidly reacted with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 minutes, the reaction of the resulting solution was stopped while maintaining the temperature below 25 ° C. in 3 N HCl (196 L, 589 mol). After removing the aqueous phase, about 200 L of solvent was distilled off to concentrate the organic solution. Acetic acid (352 kg) was added while distilling 325 kg of solvent in 100 mm vacuum. After cooling the solution to 30 ° C., 12 N HCl (43.4 kg, 434 mol) was added and the mixture was heated to 65-70 ° C. and maintained for 4 hours. The resulting slurry was cooled to 5 ° C. and the product collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a white crystalline solid.

Example 3 Preparation of N-((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline

To a slurry of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate (40.0 kg, 144 mol) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to a pH of 7.0. It was. After removal of the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was heated to reflux to distill the water / toluene azeotrope mixture (30 L). The solution was cooled to room temperature and washed with saturated brine (80 kg). The organic solution was concentrated in vacuo to a volume of 35-40 L and then diluted with THF (52 kg). The weight percent of the title compound in toluene / THF was 43% as calculated by HPLC. The yield based on HPLC weight% was 47.7 kg (96%). The solvent was removed in vacuo and recrystallized from heptane to give a sample for analysis.

Example 3a : Synthesis of (1R, 2S) -pyrrolidinyl norephedrine

To a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 mol) was added (1R, 2S) -norephedrine (68.6 kg, 454 mol). The mixture was heated to 90 ° C. and 1,4-dibromobutane (113.4 kg, 525 mol) was added over 2 hours. The reaction was refluxed for 5 hours and then cooled to 40 ° C. Water (181 kg) was added and the phases separated at 30 ° C. 12 N HCl (54.3 kg, 543 mol) was added to the organic phase. The solution was heated to reflux and 150 L of distillate was removed in a vacuum of 200 to 300 mm. Toluene (39.5 kg) was added at 70 ° C and the resulting slurry was cooled to 0-5 ° C for crystallization. The product was collected, washed twice with toluene (39 kg each) and dried under nitrogen purge to give 83.6 kg of the title compound as a hydrochloride salt. This hydrochloride salt was added to toluene (392 kg) and water (42 kg) and treated with 30% NaOH (about 55 kg, 414 mol) to bring the pH above 12. After removal of the lower water phase, the organic solution was partially concentrated by distillation of 140 L of solvent to give 20% by weight of the title compound solution in toluene. The calculated yield was 50 kg (75%). The toluene solution of the title compound was concentrated in vacuo and then recrystallized from heptane to give an analytical sample. Melting point: 46-48 ° C.

Example 3b Preparation of Cyclopropylacetylene

A mixture of 5-chloro-1-pentine (23.0 kg, 224 mol) and anhydrous THF (150 kg) was cooled to -20 ° C. To the mixture was added n-hexyllithium (2.3 equiv, 30 wt% 158 kg) in hexane (about 2 hours) without the temperature exceeding 5 ° C. In the latter half of the time of n-hexyllithium, the temperature should be kept above -5 ° C to prevent the accumulation of organo lithium and dangerous exothermic induction reactions. The reaction was aged at −5 to 0 ° C. for 2 hours until GC analysis showed over 99% conversion. Toluene (35-40 kg) was then added and the reaction concentrated under vacuum until reduced to about one third of the original volume. Upon concentration the mixture was heated (up to about 40 ° C.) to maintain a good distillation rate. The mixture was then cooled to 15-20 C and a solution of ammonium chloride (11-12 kg) in 50-60 L of water was added at a rate not exceeding 10 캜. After separating the aqueous layer (approximately 70 kg), the reaction mixture is circulated through a tower containing 15 kg of 3 μg molecular sieves until the moisture content is measured to less than about 300 ppm by Karl Fisher analyzer. I was. The dried organic solution was then distilled through a column packed with steel wool at atmospheric pressure and cyclopropylacetylene was collected as a solution in THF / toluene / hexanes. The calculated yield was 14.0 kg.

Example 4 Preparation of (S) -5-Chloro-α- (cyclopropylethynyl) -2-[(4-methoxyphenyl) methyl] -amino] -α- (trifluoromethyl) benzenemethanol

Toluene solution of (1R, 2S) -pyrrolidinyl norephedrine (including 80 kg, 60.7 mol of (1R, 2S) -pyrrolidinyl norephedrine) was charged with triphenylmethane (100 g). This solution was concentrated in vacuo to about half of the original volume. Anhydrous THF (35 kg) was added and the solution was chilled with a cooling jacket set at -50 ° C. When the temperature reached -20 ° C, n-hexyllithium (33% by weight in hexanes, 33.4 kg, 119.5 mol) was charged while maintaining the temperature below 0 ° C. While maintaining the internal temperature below −20 ° C., the resulting red solution was charged with a cyclopropylacetylene solution (about 4 kg, 30% by weight in THF / hexane / toluene containing 65 mol of cyclopropylacetylene). The resulting solution was aged at -45 to -50 ° C for 1 hour. While maintaining the reaction temperature below −40 ° C., the N-((4′-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline solution (about 10 kg, 28.8 mol of N-) was added to the cold solution. (43% by weight in THF / toluene containing (4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline) was charged. The mixture was aged at -43 ± 3 ° C for 1 hour, and then placed in 140 kg of 1N HCl, which was previously cooled to 0 ° C, to stop the reaction. The organic layer was separated, extracted twice with 25 kg portions of 1N HCl and twice with 40 kg of water, then concentrated in vacuo to a volume of about 29 L. Toluene (47 kg) was added and the solution was concentrated to a volume of 28-30 L. Heptane (23 kg) was charged and the mixture was cooled and maintained at -5 ° C for 4 hours. The product was filtered, washed twice with 10 kg parts of heptane and dried in vacuo to give 10 kg (85%) of the title compound as an off-white solid.

Example 5 : (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'-methoxyphenyl) -3, Preparation of 1-benzoxazine

To a solution of heptane (295.5 kg) and ethyl acetate (32.5 kg) p-chloranyl (57 kg, 232 mol) and (S) -5-chloro-α- (cyclopropylethynyl) -2-[(4- Methoxyphenyl) methyl] -amino] -α- (trifluoromethyl) benzenemethanol (89 kg, 217 mol) was added. The mixture was refluxed for 5.5 hours with good stirring, then diluted with ethyl acetate (64.1 kg) and cooled to 30 ° C. Tetrachlorohydroquinone was removed by filtration and washed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). 260 L of solvent was distilled off to partially concentrate the filtrate, then diluted with heptane (177 kg) and cooled to -10 to -15 ° C. The resulting slurry was filtered and the product was washed with heptane (41 kg) and then dried over a filter to less than 20% by weight (by loss on drying). The yield calculated by HPLC was 71 kg (80%). The sample was triturated with 1 N NaOH and recrystallized from hexane / ethyl acetate to give an analytical sample. Melting point: 130-131.7 ° C.

Example 6 (S) -5-Chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzenemethanol

To a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61 L) crude (S) -5-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- ( Trifluoromethyl) -2- (4'-methoxyphenyl) -3,1-benzoxazine (71 kg dry weight) was charged. The mixture was heated to 60 ° C to give a clear solution, which was cooled to 30 ° C. While maintaining the temperature below 35 ° C., a solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29 L) was added to the methanol solution over 20 minutes. After 30 minutes, the reaction of excess borohydride with acetone (5.8 kg) was stopped and the solution was diluted with water (175 L) and neutralized to pH 8-9 with acetic acid. The resulting slurry was cooled to about 0 ° C and filtered, then the product was washed with water and dried in vacuo at 40 ° C. The crude product was slurried again with a mixture of toluene (133 kg) and heptane (106 kg), initially cooling at 25 ° C. and later below −10 ° C. The product was filtered off, washed with heptane (41 kg) and dried in vacuo at 40 ° C. to give 44.5 kg (88%) of an off-white / light yellow crystalline solid. Analytical samples were recrystallized from t-butyl methyl ether / heptane.

Example 7 : (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one Manufacture

Below -10 ° C, (S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzene in a mixture of heptane (32 kg) and THF (52 kg) Methanol (15.7 kg, 54.3 mol) was dissolved. Phosgene (about 8.0 kg, 80 mol) was added directly below the surface over about 1 hour while maintaining the temperature below 0 ° C. The resulting slurry was warmed to 20-25 ° C. and maintained for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred for about 30 minutes. Heptane (97 kg) was added and about 140 L of solvent was distilled off under reduced pressure. Heptane (97 kg) and THF (22 kg) were added and the solution was washed with 5% aqueous sodium bicarbonate (15 L) followed by water (15 L). The solution was warmed to 50 ° C. and filtered through a clear reaction vessel and washed with 40 kg heptane. The solution was concentrated under reduced pressure and diluted with heptane (22 kg) and then cooled to below -10 ° C. The product was filtered off, washed with heptane (37 kg) and dried in vacuo at 90-100 ° C. to give 16.0 kg (95%) of an off-white to slightly pink solid. HPLC: 99.8 area%.

Examples 8 to 16 relate not only to the manufacturing method of each form for the efavilens of the present invention, but also to a method of switching these forms with each other. The following examples are intended to illustrate the invention and should not be understood as limiting the scope of the invention.                 

Example 8 Direct Crystallization of Form 1

Epavirens (800 g, 2.5 mol) was dissolved in THF (1.2 L) and heptane (68 L). This solution was filtered through Whatman filter paper 1 to make it clear. The volume was then kept constant by distillation at atmospheric pressure to remove THF and replacing with fresh heptane. When the amount of THF was less than 1%, the solution was cooled to 70 ° C. and seeded. The solution was further cooled and crystallization started at 64 ° C. XRD confirmed the sample to be Form 1. The slurry was further cooled to 30 ° C. and filtered. The wet cake was dried at 65 ° C. in a vacuum oven with nitrogen purge until the loss by drying was 0.36% to give 640 g (80% yield) of the product.

Example 9 Crystallization of Form 2 and Conversion to Form 1

Epavirens (450 g, 1.4 mol) was slurried in heptane (3.5 L) and heated to reflux until completely dissolved. The solution was left to cool to 73 ° C. and at this point was filtered through Whatman filter once and then cooled to 6 ° C. The diluted slurry was filtered and the wet cake was washed with 300 mL of heptane. The wet cake (389 g) was dried in a vacuum tray oven at 100 ° C. for 15 hours to give 388 g (86% yield) of crystalline form 1.

Example 10 Crystallization of Form 4 and Conversion to Form 1

Efavirens (32 g, 0.1 mol) were dissolved in 390 mL of heptane and 20 mL of THF at 60 ° C. The solution was allowed to cool down and seeded with 50 mg of DMP 266 at 45 ° C. After crystals formed, the solvent was removed in vacuo and replaced with fresh heptane. The slurry was cooled to 0 ° C. and filtered. It confirmed that it was Form 4 by XRD. It was dried for 16 h at 80 ° C. in a vacuum oven to give 26 g (82% yield) of crystalline form 1.

Example 11 Crystallization of Form 2, Conversion to Form 3, and Conversion to Form 1

Efavirens (105 g, 0.33 mol) were slurried in 1.2 L of heptane and heated to reflux until dissolved. The solution was allowed to cool to 75 ° C., filtered through Whatman filter once and then cooled. The thin slurry was crystallized and the sample was filtered. It was confirmed that it was Form 2 by X-ray powder diffraction. The slurry was stirred at room temperature for 24 hours, the resulting thick slurry was diluted with 200 mL of heptane, filtered and dried in vacuo at room temperature to give 82.5 g (79%). X-ray powder diffraction identified this solid as crystalline Form 3. 5 g of the sample was dried at 90 ° C. for 24 hours and it was confirmed that the solid produced by X-ray powder diffraction was crystalline Form 1.

Example 12 Conversion from Form 1 to Form 3

Epavirens crystalline Form 1 (105 g, 0.33 mol) was slurried at room temperature in 1.0 L of heptane for 7 days. XRD confirmed the absence of Form 1 at all in the sample. The peaks obtained were identical to the pickies obtained starting from Form 2, although the relative intensities were slightly different.

Example 13 Conversion from Form 2 to Form 4

Epavirens Crystal Form 2 (50 g, 0.16 mol) was slurried in 580 mL of heptane. THF (7 mL, resulting in 1% THF in heptane) was added and heated to 40 ° C. to filter the slurry sample after 50 minutes and XRD (X-ray powder diffraction) confirmed that this sample was still Form 2 It was. THF (28 mL was added to give a total of 32 mL, resulting in 5% THF in heptane) in 4 portions. After the last portion was added the mixture was cooled to 28 ° C., at which point a very thick slurry formed, which was determined to be Form 4 by XRD.

Example 14 Conversion from Form 1 to Form 4

Epavirens crystalline Form 1 (10 g, 0.03 mol) was slurried in 900 mL of heptane. This slurry was heated to 35 ° C. THF was added to 2 mL portions. A total of 6 mL (which results in about 6% THF solution) was added and the slurry became very thick. It confirmed that it was Form 4 by XRD.

Example 15 Conversion from Form 2 to Form 1 by Slurry Heating at 70 ° C

Epavirens Crystal Form 2 (3 g, 0.01 mol) was slurried in heptane (42 mL), then heated to 70 ° C. and maintained for 2 hours. The temperature of this slurry was allowed to cool down to room temperature and the sample was filtered for XRD analysis, after which XRD confirmed that only Form 1 was present.

Example 16 Conversion from Form 3 to Form 1 by Slurry Heating at 70 ° C

Epavirens Crystal Form 3 (3 g, 0.01 mol) was slurried in heptane (42 mL) for 48 hours. It confirmed that it was Form 3 by XRD. This slurry was then heated to 70 ° C. and maintained for 2 hours, cooled to room temperature, and then filtered for sample for XRD analysis to determine that it was Form 1.

Example 17 Direct Crystallization of Form 5

Epavirens crystalline Form 1 (about 70 g) was slurried in 1 L of THF / heptane (1%, v / v) at room temperature. Undissolved solids were removed by filtration and the mother liquor was seeded into Form 5 at room temperature. Slowly forming crystals were isolated by filtration to yield 0.92 g of Form 5. X-ray powder diffraction identified this solid as crystalline Form 5.

Alternatively, Epavirens Crystal Form 1 (about 70 g) was slurried in 1.5 L of THF / heptane (1%, v / v) and warmed to 40 ° C. The solution was filtered at warm state (40 ° C.) to remove undissolved solids, and the mother liquor was seeded into Form 5 at 40 ° C. As the solution was cooled to room temperature, Form 5 crystallized. This solid was isolated by filtration at room temperature (9.43 g).

Alternatively, efavirenz crystalline Form 1 (about 70 g) was slurried in 1 L of warmed heptane and 10 mL of THF was added so that the solvent ratio was 1% (v / v) of THF / heptane. Then, this slurry was heated to 85 degreeC, and all were dissolved. While cooling this solution, the seeds were periodically seeded into Form 5 until the seeds were no longer dissolved (63 ° C.), then cooled to 45 ° C. and filtered. Isolated solid was Form 1 This solution was then allowed to cool to room temperature overnight and Form 5 was collected by filtration (15.41 g).

Example 18 Conversion of Form 5 to Form 1

Form 5 was dried at 95 ° C. for 3 days in a vacuum oven with a nitrogen purge to afford the compound identified as Form 1 by X-ray powder diffraction.

Claims (69)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete X-ray powder diffraction including at least four 2θ values selected from the group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2 Form 2 compound of crystalline Efavirenz, characterized by a pattern. The compound of claim 21, wherein the purity is greater than 90%. delete delete 22. The compound of claim 21, characterized by a differential scanning calorimetry thermogram with a peak at 116 ° C to 119 ° C. delete delete A pharmaceutical composition for inhibiting human immunodeficiency virus replication by a reverse transcriptase encoded by a human immunodeficiency virus, comprising an effective inhibitory amount of the compound of claim 21. A pharmaceutical composition for treating a human immunodeficiency virus infection comprising a therapeutically effective amount of the compound of claim 21. The composition of claim 29, wherein the compound is present at a dosage of 1 mg to 1000 mg. delete delete 1) dissolving efavirens in heptane at a temperature of 70 ℃ to 80 ℃ to obtain a saturated solution, 2) filtering the saturated solution, and 3) producing crystalline Form 2 of the crystalline epabilens by rapid cooling of the saturated solution, including contact with the cold surface of the saturated solution The manufacturing method of the crystalline form 2 of the crystalline efavi lens of claim 21 by the rapid crystallization method comprising a. delete 1) adding heptane to a solution of epavirens in tetrahydrofuran to produce a final solution, 2) distilling the final solution with 1-10% tetrahydrofuran in heptane to crystallize the efavirens to crystalline Form 4, and 3) isolating the crystal (the isolation step comprises filtration) Differential scanning calorimetry method having a peak at 95 ℃ to 100 ℃ comprising a thermal analysis, characterized in that the manufacturing method of Epavilens Crystal Form 4. Group consisting of 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2, 20.6 ± 0.2, 21.3 ± 0.2, 22.8 ± 0.2, 24.8 ± 0.2, 27.4 ± 0.2, 28.2 ± 0.2 and 31.6 ± 0.2 5. A crystalline form of crystalline evivirens characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from 5. The compound of claim 36, wherein the purity is greater than 90%. 37. The compound of claim 36, characterized by a differential scanning calorimetry thermogram with a peak at 108 ° C to 110 ° C. A pharmaceutical composition for inhibiting human immunodeficiency virus replication by a reverse transcriptase encoded by a human immunodeficiency virus, comprising an effective inhibitory amount of the compound of claim 36. A pharmaceutical composition for treating a human immunodeficiency virus infection comprising a therapeutically effective amount of the compound of claim 36. The composition of claim 40, wherein the compound is present at a dosage of 1 mg to 1000 mg. 37. The compound of claim 36, prepared by recrystallization from a mixed solvent system comprising tetrahydrofuran and a hydrocarbon. Of therapeutically effective amounts (a) the compound of claim 21 or 36, and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors Including, pharmaceutical combination formulation for the treatment of HIV infection. Differential Scanning Calorimetry with Peaks at 116 ° C. to 119 ° C. Crystalline Form 2. 45. The compound of claim 44, wherein the purity is greater than 90%. delete delete A pharmaceutical composition for inhibiting human immunodeficiency virus replication by a reverse transcriptase encoded by a human immunodeficiency virus, comprising an effective inhibitory amount of the compound of claim 44. A pharmaceutical composition for treating a human immunodeficiency virus infection comprising a therapeutically effective amount of the compound of claim 44. The composition of claim 49, wherein the compound is present at a dosage of 1 mg to 1000 mg. delete delete 1) dissolving efavirens in heptane at a temperature of 70 ℃ to 80 ℃ to obtain a saturated solution, 2) filtering the saturated solution, and 3) The crystallinity of claim 44, comprising the step of producing crystalline Form 2 of the crystalline epabilens by rapid cooling of the saturated solution, including contact with the cold surface of the saturated solution. The manufacturing method of the crystalline form 2 of a parvi lens. delete 1) adding heptane to a solution of epavirens in tetrahydrofuran to produce a final solution, 2) distilling the final solution with 1-10% tetrahydrofuran in heptane to crystallize the efavirens to crystalline Form 4, and 3) isolating the crystal (the isolation step comprises filtration) Including, 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2 and 24.3 ± 0.2 A method for producing Epavirens crystalline Form 4, characterized by an x-ray powder diffraction pattern comprising at least four 2θ values selected from: Differential scanning calorimetry with peaks at 108 ° C. to 110 ° C. Crystalline Form 5. The compound of claim 56, wherein the purity is greater than 90%. delete A pharmaceutical composition for inhibiting human immunodeficiency virus replication by a reverse transcriptase encoded by a human immunodeficiency virus, comprising an effective inhibitory amount of the compound of claim 56. A pharmaceutical composition for treating a human immunodeficiency virus infection comprising a therapeutically effective amount of the compound of claim 56. 61. The composition of claim 60, wherein the compound is present at a dosage of 1 mg to 1000 mg. The compound of claim 56 prepared by recrystallization from a mixed solvent system comprising tetrahydrofuran and a hydrocarbon. Of therapeutically effective amounts (a) the compound of claim 44 or 56, and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors Including, pharmaceutical combination formulation for the treatment of HIV infection. delete delete delete 1) crystallizing Form 4 of crystalline efavirenz from a solution of tetrahydrofuran / heptane in which the concentration of tetrahydrofuran is 5% and the concentration is lowered to 1%, 2) heating crystalline form 4 of the crystalline efavirenz to a temperature of 80 ° C to 100 ° C; 4, selected from the group consisting of 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2, 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 ± 0.2 and 24.8 ± 0.2, including A method for producing crystalline evivirens crystal form 1, characterized by an x-ray powder diffraction pattern comprising at least 2θ values. 1) crystallizing Form 4 of crystalline efavirenz from a solution of tetrahydrofuran / heptane in which the concentration of tetrahydrofuran is 5% and the concentration is lowered to 1%, 2) heating crystalline form 4 of the crystalline efavirenz to a temperature of 80 ° C to 100 ° C; Differential scanning calorimetry method having a peak at 138 ℃ to 140 ℃ comprising a thermal analysis diagram, characterized in that the manufacturing method of crystalline epavilens crystal Form 1. delete

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